Alterations in the X-linked protocadherin-19 (PCDH19) gene cause a rare form of epilepsy, along with challenges in both cognitive and sensory processing, and autism spectrum disorder (ASD). While males with mutations in their sole PCDH19 copy often show no features of the disorder, 90 percent of heterozygous females carrying alterations in only one PCDH19 copy do show features. In work supported by a Pilot Award to SFARI Investigator Hisashi Umemori, data from a mouse model of Pcdh19 disorder provides further evidence that this female bias is due to changes in the ability of the PCDH19 protein to promote the development and function of neuronal synaptic contacts (Hoshina et al., Science, 2021).
The PCDH19 gene is located on the X chromosome. In females, genes on the X chromosome undergo a process of random suppression called X inactivation. When only a single copy of an X-linked gene is altered, such as in females with PCDH19 disorder, X inactivation results in a patchy mosaic pattern of gene expression – whereby some cells have a functional copy of the gene while others have the altered form. PCDH19 encodes a cell-cell adhesion protein expressed in the brain and, through an extracellular region of the protein, promotes synapse interactions to support communication between neurons. Prior work had shown that mosaic expression of Pcdh19 in female mouse cortical neurons altered cell-cell adhesion properties and overall brain activity, whereas complete loss of Pcdh19 did not cause these effects (Pederick et al., Neuron, 2018).
In the new study, Umemori’s laboratory found that the Pcdh19 protein is present in the mossy fiber region of the hippocampus, a brain area critical for memory, and that Pcdh19 heterozygous female mice had specific alterations in mossy fiber-based memory processing (pattern completion and separation) but not other hippocampal-based memory processes. Using a cell culture system, the group found that mosaic expression of Pcdh19 caused alterations in extracellular interactions between the Pcdh19 protein and a second cadherin (N-cadherin) leading to defects in presynaptic development. Further, female mice with only one copy of Pcdh19 demonstrated a defect in mossy fiber presynaptic signaling, exhibiting reductions in N-cadherin signaling, smaller presynaptic ends and decreases in neurotransmitter release and electrical responses (LTP). These effects were reversed when the researchers increased expression of N-cadherin in presynaptic mossy fiber terminals of Pcdh19 heterozygous mice. Combined with prior work, these data indicate that X-inactivation-based mosaic expression of PDCH19 alters N-cadherin-based signaling in the brain and underlies the female-specific bias in PCDH19 disorder.
Female-specific synaptic dysfunction and cognitive impairment in a mouse model of PCHD19 disorder.
Hoshina N., Johnson-Venkatesh E.M., Hoshina M., Umemori H.